Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients

// Irene Baccelli 1 , 2 , * , Albrecht Stenzinger 3 , * , Vanessa Vogel 1 , 2 , 3 , Berit Maria Pfitzner 4 , Corinna Klein 1 , 2 , Markus Wallwiener 5 , Martina Scharpff 5 , Massimo Saini 1 , 2 , Tim Holland-Letz 6 , Hans-Peter Sinn 3 , Andreas Schneeweiss 5 , Carsten Denkert 4 , 7 , Wilko Weichert 3 , 5 , 7 , * , Andreas Trumpp 1 , 2 , 7 , * 1 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 2 Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 3 Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany 4 Institute of Pathology, Charite Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany 5 National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany 6 Department of Biostatistics, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld TP4, 69120 Heidelberg, Germany 7 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany * These authors contributed equally to the study Correspondence to: Dr. Andreas Trumpp e-mail: a.trumpp@dkfz-heidelberg.de or andreas.trumpp@hi-stem.de Keywords: breast cancer, prognosis, biomarker, CD47, MET, metastasis, circulating tumor cells, metastasis-stem cell. Received: June 26, 2014      Accepted: August 23, 2014      Published: September 02, 2014 ABSTRACT Although luminal-type primary breast cancer can be efficiently treated, development of metastatic disease remains a significant clinical problem. We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts. Here, we investigated the clinical relevance of MET-CD47 co-expression in 255 hormone receptor positive breast tumors by immunohistochemistry and found a 10.3-year mean overall-survival difference between MET-CD47 double-positive and double-negative patients (p<0.001). MET-CD47 co-expression defined a novel independent prognosticator for overall-survival by multivariate analysis (Cox proportional hazards model: HR: 4.1, p<0.002) and CD47 expression alone or in combination with MET was strongly associated with lymph node metastasis. Furthermore, flow cytometric analysis of metastatic patient blood revealed consistent presence of MET+CD47+ CTCs (range 0.8 - 33.3% of CTCs) and their frequency was associated with increased metastatic spread. Finally, primary uncultured CTCs with high MET+CD47+ content showed an enhanced capacity to initiate metastasis in mice. Detection and targeting of MET and CD47 may thus provide a rational basis for risk stratification and treatment of patients with luminal-type breast cancer.